Design of a “Mini” Nucleic Acid Probe for Cooperative Binding of an RNA-Repeated Transcript Associated with Myotonic Dystrophy Type 1

• Published in: Biochemistry (Easton) 2018-02, Vol.57 (6), p.907-911
• Main Authors: Hsieh, Wei-Che, Bahal, Raman, Thadke, Shivaji A, Bhatt, Kirti, Sobczak, Krzysztof, Thornton, Charles, Ly, Danith H
• Format: Article
• Language: English
• Subjects: Base Sequence; Binding Sites; Humans; Myotonic Dystrophy - genetics; Myotonic Dystrophy - metabolism; Myotonin-Protein Kinase - genetics; Myotonin-Protein Kinase - metabolism; Peptide Nucleic Acids - chemistry; Peptide Nucleic Acids - genetics; Peptide Nucleic Acids - metabolism; RNA - chemistry; RNA - genetics; RNA - metabolism; RNA Probes - chemistry; RNA Probes - genetics; RNA Probes - metabolism; RNA-Binding Proteins - metabolism; Trinucleotide Repeat Expansion
• ISSN: 0006-2960; 1520-4995
• DOI: 10.1021/acs.biochem.7b01239

Toxic RNAs containing expanded trinucleotide repeats are the cause of many neuromuscular disorders, one being myotonic dystrophy type 1 (DM1). DM1 is triggered by CTG-repeat expansion in the 3′-untranslated region of the DMPK gene, resulting in a toxic gain of RNA function through sequestration of MBNL1 protein, among others. Herein, we report the development of a relatively short miniPEG-γ peptide nucleic acid probe, two triplet repeats in length, containing terminal pyrene moieties, that is capable of binding rCUG repeats in a sequence-specific and selective manner. The newly designed probe can discriminate the pathogenic rCUGexp from the wild-type transcript and disrupt the rCUGexp–MBNL1 complex. The work provides a proof of concept for the development of relatively short nucleic acid probes for targeting RNA-repeat expansions associated with DM1 and other related neuromuscular disorders.